Nivolumab Plus Chemotherapy Improves Survival in Advanced Gastric and Esophageal Adenocarcinomas: Now to Figure Out the Details in These Heterogeneous Diseases

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There is no doubt that subsets of patients with esophageal and gastric cancers benefit from immune checkpoint inhibitor therapy. The complexity lies in identifying the appropriate histology, tumor location, expression of programmed cell death receptors and ligands, mechanism of checkpoint inhibition, and concomitant therapy. The multi-institution study of nearly 1,600 randomly assigned patients in CheckMate 649—reported in The Lancet by Janjigian et al1 and summarized in this issue of The ASCO Post—provides an opportunity to explore some of these nuances.

CheckMate 649 assessed the addition of first-line nivolumab to chemotherapy in patients with advanced non-HER2–positive adenocarcinomas, regardless of PD-L1 expression, of which 70% arose from the stomach, 16% arose from the gastroesophageal junction, and 13% arose from the esophagus. Tumor cell PD-L1 expression of at least 1% was detected in just 16% of cases using the validated Dako PD-L1 immunohistochemistry 28-8 pharmDx assay for gastric, gastroesophageal, and esophageal adenocarcinomas. During study enrollment, it became clear that the combined positive score (CPS) provided a better predictive marker for response to therapy. The CPS is generated by identifying PD-L1 expression in tumor cells, lymphocytes, and macrophages, dividing by the total number of viable tumor cells, and multiplying by 100.

“There is no doubt that subsets of patients with esophageal and gastric cancers benefit from immune checkpoint inhibitor therapy.”
— Mary F. Mulcahy, MD

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It is important to note that the CPS score has been validated for gastric cancer using the 22C3 pharmDx assay, not the 28-8 assay used in this study.2 Although high concordance rates have been demonstrated between the 28-8 and 22C3 assays across a range of tumor types, validation in gastric cancer and standardization of testing would benefit future research and clinical utility.3

The overall survival benefit was demonstrated for all randomly assigned patients with the addition of nivolumab to chemotherapy. However, it was more robust for the 60% of patients with a PD-L1 CPS of at least 5 (hazard ratio [HR] = 0.71, P < .0001) as compared with the group that included those with a PD-L1 CPS of at least 1 (HR = 0.77, P < .0001) or all patients (HR = 0.80, P = .0002).

HER2 Expression and MSI-H Phenotype

Up to 40% of patients randomly assigned in CheckMate 649 had an unknown HER2 expression status, balanced among treatment groups. With an expected HER2-positivity rate of approximately 20% in gastric and esophagogastric cancers, it would be expected that approximately 8% of patients could have had HER2 expression. The inclusion of these patients would not be expected to alter the results of this study, especially considering the recent interim analysis of the KEYNOTE-811 study.4

KEYNOTE-811 enrolled patients with HER2-expressing gastric and gastroesophageal adenocarcinomas to receive pembrolizumab or placebo with trastuzumab, fluoropyrimidine, and platinum; it demonstrated a statistically significant benefit in overall response rate in the pembrolizumab-containing arm (74% vs 52%, P < .0001). The results of this interim analysis have led to accelerated approval by the U.S. Food and Drug Administration of pembrolizumab with trastuzumab and chemotherapy in first-line therapy for HER2-expressing gastric and gastroesophageal adenocarcinomas.

“Further investigation of MSI-H tumors that do not respond to checkpoint inhibitors may identify more specific predictive or resistance markers.”
— Mary F. Mulcahy, MD

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Approximately 3% of patients in CheckMate 649 had a DNA mismatch repair defect leading to a microsatellite instability–high (MSI-H) phenotype. At the time of study closure, median overall survival had not been reached for this cohort of patients. Of the 44 patients with MSI-H tumors, 10 had a PD-L1 CPS of less than 5. Across all tumor types, checkpoint inhibition has been shown to be a preferred approach for treating patients with MSI-H tumors, despite other surrogate predictive markers. Further investigation of MSI-H tumors that do not respond to checkpoint inhibitors may identify more specific predictive or resistance markers.

Gastric and gastroesophageal adenocarcinomas are complex and heterogeneous diseases. At the time of diagnosis, it is imperative to obtain evaluation of DNA mismatch repair defects, HER2 expression, and PD-L1 CPS. Although the fluoropyrimidine and platinum chemotherapy backbone


For more on the treatment of gastric and esophageal cancers, see a joint interview with Mary F. Mulcahy, MD, and Crystal S. Denlinger, MD, on The ASCO Post Newsreels at

has not changed, the addition of targeted agents has demonstrated prolonged survival. As demonstrated in CheckMate 649, the median overall survival for those patients with a PD-L1 CPS of at least 5 was 14.4 months. For patients with HER2 expression, the addition of trastuzumab in the first line of therapy resulted in a median overall survival of 13.8 months.5 Recently, trastuzumab deruxtecan in the second line has demonstrated a median overall survival of 12.5 months in patients previously treated with HER2 inhibitors.6 The survival benefit of trastuzumab and pembrolizumab in HER2-positive, PD-L1–expressing tumors remains to be seen.

What Next?

CheckMate 649 is an important and practice-changing study. Ongoing research is evaluating new therapeutics, targets, and pathways. As the treatment of gastric and gastroesophageal cancers evolves, it is foreseeable that resistance to therapy will occur. Identifying the resistance mechanisms and markers of resistance will spare patients unnecessary toxicity, including cost. Our patients will benefit from a robust and comprehensive research platform. 

Dr. Mulcahy is a medical oncologist employed at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University, Chicago.

DISCLOSURE: Dr. Mulcahy has received research funding from BTG.


1. Janjigian YY, Shitara K, Moehler M, et al: First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial. Lancet 398:27-40, 2021.

2. Kulangara K, Zhang N, Corigliano E, et al: Clinical utility of the combined positive score for programmed death ligand-1 expression and the approval of pembrolizumab for treatment of gastric cancer. Arch Pathol Lab Med 143:330-337, 2019.

3. Krigsfeld GS, Prince EA, Pratt J, et al: Analysis of real-world PD-L1 IHC 28-8 and 22C3 pharmDx assay utilisation, turnaround times and analytical concordance across multiple tumour types. J Clin Pathol 73:656-664, 2020.

4. Chung HC, Bang YJ, Fuchs CS, et al: First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811. Future Oncol 17:491-501, 2021.

5. Bang YJ, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 376:687-697, 2010.

6. Shitara K, Bang YJ, Iwasa S, et al, DESTINY-Gastric01 Investigators: Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med 382:2419-2430, 2020.

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